Diabetes mellitus and its complications are now considered to be the third leading cause of death in Canada and the United States, trailing only cancer and cardiovascular disease. According to a report issued by the National Commission on Diabetes, as many as 10 million North Americans may have diabetes, and the incidence is increasing yearly. Although the acute and often lethal symptoms of diabetes can be controlled by insulin therapy, the long-term complications reduce life expectancy by as much as one third. Compared with rates of incidence in nondiabetic normal persons, diabetic patients show rates which are increased 25-fold for blindness, 17-fold for kidney disease, 5-fold for gangrene, and 2-fold for heart disease.
There are 2 major forms of diabetes mellitus. One is type I diabetes, which is also known as insulin-dependent diabetes mellitus (IDDM), and the other is type II diabetes, which is also known as noninsulin-dependent diabetes mellitus (NIDDM). Most patients with IDDM have a common pathological picture: the nearly total disappearance of insulin-producing pancreatic beta cells which results in hyperglycemia .sup.1-7.
Considerable evidence has been accumulated showing that most IDDM is the consequence of progressive beta-cell destruction during an asymptomatic period often extending over many years .sup.1-7. The prediabetic period can be recognized by the detection of circulating islet-cell autoantibodies and insulin autoantibodies. The hypothesis that IDDM is an autoimmune disease has been considerably strengthened by studies on the nonobese diabetic (NOD) mouse .sup.8-12 and the BioBreeding (BB) rat .sup.13-27. Both of these animals develop IDDM spontaneously and their diabetic syndromes share many pathological features with that of humans with IDDM.
Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), is much more common than IDDM, affecting 90% of all persons with diabetes. NIDDM is a mild form of diabetes, often of gradual onset, which usually appears in middle age (over 40 years of age). The pathological changes in the pancreatic islets in patients with NIDDM are not always apparent. Moreover, the clinical manifestations of NIDDM are frequently mild, and high glucose levels in the blood can usually be controlled by diet alone. Although diabetes is traditionally viewed as a condition caused by a deficiency of insulin, many patients with NIDDM have normal to high plasma insulin levels. In these individuals, diabetes arises not from a shortage of insulin, but probably from a defect in the molecular machinery that medicates the action of insulin on its target cells.
A number of hypotheses have been put forward to explain NIDDM, including insulin resistance, down regulation of insulin receptors, and problems with the glucose transport system. In NIDDM, insulin resistance results in a reduction in the biological response to insulin of about 40%. Insulin lowers blood glucose through two separate mechanisms, namely, by suppressing glucose release from the liver, and by promoting uptake of glucose in the peripheral tissues, particularly muscle. In NIDDM, the responsiveness of peripheral tissues to insulin is substantially impaired.sup.59. There are also some data suggesting that hepatic glucose output is less easily suppressed by insulin in NIDDM, implying that the liver shares in the insulin resistance.sup.60. Hyperglycemia itself can also cause insulin resistance and impaired insulin secretion, but many factors also contribute to the insensitivity including obesity, age, lack of exercise, diet and genetic components. The mechanisms of insulin resistance in NIDDM are unclear but may involve reduced insulin receptor numbers (secondary to hyperinsulinaemia and hyperglycemia), reduced tyrosine kinase of the insulin receptors, and abnormalities distal to the receptors.
The major intracellular actions of insulin are stimulation of both nutrient uptake and biosynthetic processes. Glucose uptake is enhanced by increasing glucose transporters on the cell surface, probably by promoting their translocation from intracellular pools. NIDDM may occur because of a decreased number of glucose transporters on the target cell surface. If this is so, NIDDM is not caused by beta cell destruction, but by other mechanisms.
The GK rat is considered to be one of the best animal models for NIDDM, and is characterized by impaired glucose-insulin secretion and peripheral insulin resistance.sup.61,62. Insulin response and sensitivity of glycogen synthesis, lipogenesis and DNA synthesis in hepatocytes from GK rats are markedly reduced as compared to non-diabetic control rats such as Wistar-Furth (WF). Insulin binding activity in adipocytes and hepatocytes from the GK rat are not different from those of control rats, suggesting that insulin resistance might result from a post-binding defect. Insulin-induced generation of inositol glycan is also markedly reduced in adipocytes and hepatocytes from the GK rat as compared with non-diabetic control WF rats. Two inositol anomers, myo-inositol and chiro-inositol are essential components of inositol glycans. The urinary secretion of chiro-inositol in GK rats in much lower than in control rats. In contrast, the urinary secretion of myoinositol is higher in the GK rat than in control rats. On the basis of these results, Suzuki et al..sup.63 suggest that reduced generation of inositol glycan and altered metabolism of inositol anomers may contribute to the post-binding defect in insulin resistance in the GK rat.
Diabetes research has been directed toward prevention and cure of IDDM. To date, therapy of IDDM in humans by methods designed to suppress the autoimmune response has proved to be largely unsuccessful. Immunosuppressive therapy utilizing glucocorticoids and cyclophosphamide did not alter the course of the disease. Although studies on the use of cyclosporin A in diabetes appear to be encouraging, generalized immunosuppression involves potential complications including infections and drug-induced kidney and liver damage.
There is a need for a compound which would be nontoxic and have no side effects but which would prevent clinical IDDM and/or NIDDM completely. A preferred drug would be administered noninvasively, such as an orally administered solution or tablet.